June 2009

June 2009 Microgrants

Vascular Malformations in High Output Heart Failure in Children

Each year at British Columbia Children's Hospital (BCCH) there are 5-10 patients treated for high output heart failure (HOHF). This is a rare and serious condition in children that has a high incidence of death before one year of age. The treatments for this condition are costly and associated with many unpleasant and serious side effects.  Given the extremely low incidence of this condition, it is difficult to establish the best medical management for these cases. This study hopes to be able to provide pediatric specialists with a summary of diagnostic tools, the treatment strategies and results that might be expected. 

A comprehensive chart review of the children diagnosed with HOHF at BCCH in the last 15 years will be carried out. This should be approximately 100-200 children. The information obtained will be the largest collection of data on HOHF to date and will make an important contribution to the medical literature.

Results -

This funding supported a student to examine a very rare cause of heart failure in children: abnormal blood vessels that result in extra demands on the heart. This project identified a few risk factors for children becoming seriously ill with these blood vessel malformations. This work was published as an abstract.

The effects of droperidol and ondansetron on dispersion of myocardial repolarization in children

Long QT syndromes (LQTS) are rare, inherited diseases that predispose children to a life-threatening abnormal heartbeat (arrhythmia) called torsades des pointes. Affected patients may be asymptomatic for months or years, but if the abnormal heartbeat occurs, they effectively suffer a cardiac arrest, leading to sudden death or recovery with brain damage. The chance of torsades occurring is gauged by recording the heart's electrical activity (ECG) and measuring the QT interval. People with LQTS usually have a prolonged QT interval, but the QT interval is not good at predicting who will actually develop the dangerous arrhythmia. Another ECG measurement, Tp-e, shows more promise in predicting the risk of torsades des pointes.

In those with congenital LQTS, many drugs can make it worse. We know that having an anaesthetic and surgery is an extremely high-risk time for patients with a LQTS. Because LQTS is rare, however, we know very little about which anaesthetic drugs are safe to use and which are not. Our group has therefore been examining the QT and Tp-e intervals of normal children, to identify which anaesthetic drugs have the least effect on these measurements. Thus, when we do encounter a patient with LQTS, we can try to use drugs which will not add to their pre-existing level of risk.

In this study, we are evaluating two anti-nausea medicines, ondansetron and droperidol. Post-operative nausea and vomiting (PONV) is a common and distressing problem. Both these drugs reduce the risk of PONV. We plan to take ECGs before and after children receive anti-nausea medication during their surgery. Afterwards, we will compare the ECGs to determine whether the medicines had any significant effect on the QT and Tp-e intervals. Our findings will allow us to decide, with greater confidence, whether these medicines can be used safely in patients who do have LQTS.

Results -

This microgrant enabled our team to look at the risk of side effects on the heart when we give preventive anti-nausea drugs during anaesthesia and surgery. Post-operative nausea and vomiting is one of the more common side effects of some types of anaesthesia and surgery, and one which patients intensely dislike. Two types of drugs are well known to reduce the risk, but both are also reported - rarely - to increase the risk of abnormal heart rhythms.  Our study looked at measuring certain aspects of the heartbeat tracing [the ECG] in healthy children receiving one, or the other, or both, or neither of the anti-nausea medications. The results were very reassuring - we saw clinically unimportant changes in the heartbeat, even when both drugs were given together. This has increased our confidence in safely using either or both of these medicines to prevent or treat a common and unpleasant side effect of anaesthesia and surgery, and has helped us put the large benefit of that therapy into perspective against an extremely small risk of heart rhythm disturbances.

Identifying the genetic cause of a rare syndrome using a family's relatedness

Rare diseases affect a significant number of children in Canada. The underlying genetic cause of most of these rare disorders remains unknown.  In this pilot study we extend a proven tool for identifying the cause of inherited disease to a small family in order to understand the genetic cause of a rare unknown disorder in a pair of sisters. They both have moderate intellectual impairment and a cerebral palsy-like disorder. The parents are likely distantly related because they come from the same small village. This suggests a pattern of inheritance where both parents contribute genetic information to cause the condition. The use of a tool called "identity by descent" which looks for genetic regions that are the same in the affected sisters and different in the parents will identify the chromosomal region that is likely to contain the genetic instruction (gene) responsible for this disorder.  Identification of the chromosome region will have immediate and direct benefit for the family by providing them with a diagnosis and allowing them to make informed family planning decisions.  As a next step, the chromosome region will be searched for the specific underlying gene causing the disease in this family.  Understanding what the gene is and what it does will subsequently provide a basis to develop therapies which will help these sisters and other children with similar disorders. This study will be a trial for an approach we hope to use with other families. 

Results -

This microgrant gave us an excellent start and helped us identify a region on chromosome 1 that may carry the specific genetic change that caused this previously undescribed disorder.  With the raw data generated, further work carefully comparing each genetic instruction of the girls and their parents was done.  Using funding from other sources we were able to perform exome sequencing on the girls.  This technique looks at all the coding regions for all the genes. We were successful!  We found a genetic change in a gene located on the chromosome 1 region identified above.  This gene normally makes a product that is part of the cholesterol biosynthesis pathway, and has an important role in human development.

Genetic changes in this gene have been described in only five families to date.  The features that were seen in these sisters allow us to better understand how to recognize the condition in other families. The funds that the Rare Disease Foundation microgrant provided had significant impact in:

  • Providing the family with the relief of a definitive diagnosis.
  • Allowing genetic counselling and the option of prenatal testing should the family want more children.
  • Expanding our understanding of the features that can be seen in cholesterol pathway diseases.  There is a manuscript in preparation to share what we have learned with the medical and scientific community.
  • Offering further insight for the role of the cholesterol biosynthesis pathway in human development.

This project has been an enormous success.  We have expanded our understanding of a rare condition.  More importantly, this project has given the family hope. This project has been satisfying not only because we were able to find a diagnosis but also because we worked in partnership with the family to do so.  This is demonstrated by an e-mail from the father of the sisters while the project was underway: "Regarding pursuing further research, we are 100% backing you guys up with your further pursuit of any further test that you think might have some light at the end of the tunnel".

Using next generation sequencing to diagnose a genetic disorder in a child with a chromosomal translocation

We hope to improve the care some of the children affected by poor growth and development for whom it may be possible to treat with medication. We have characterized a new disorder of slowed development in a child with two chromosomes that broke and switched ends-called a translocation. We know that a gene necessary for bringing an important kind of sugar, called inositol, into the brain has been changed by the translocation, but we need to know in what way it has been changed. Other children may have this same problem with inositol metabolism through various mutations of the gene. We plan to take advantage of the next-generation technology available in Vancouver and rapidly sequence the translocated chromosome from end to end in one fell swoop.

Results -

The breakpoints were mapped to the SLC2A13 gene on chromosome 12 and the LOC729178 gene on chromosome 6.  Functional studies and expression arrays suggested that SLC2A13 alteration causes poor growth by altering vesicular trafficking or post-translational protein modification.

Dias, C., Huang, J.L., Lehman, A., du Souich, C., Bhatt, S., Chai, D., Eydoux, P., Stankiewicz, P., Boerkoel, C.F. SLC2A13 loss of function associated with failure to thrive and developmental delay. 60th Annual American Society of Human Genetics Meeting. November 2-6, 2010, Washington, D.C.

Lehman, A., du Souich, C., Chai, D., Bhatt, S.S., Eydoux, P., Stankiewicz, P., Van Allen, M., Boerkoel, C. Profound developmental impairment and interruption of SLC2A13: A new disorder of neuronal signaling substrate depletion? 30th Annual David W. Smith Workshop on Malformations and Morphogenesis. August 5-9, 2009. Philadelphia

Severe congenital scoliosis: which developmental signal is askew?

A family we follow has had 4 out of 4 children with a severe form of congenital scoliosis (curving collapse of the spine). Not even world experts in bone disorders have been able to identify the cause of their disability.  The children must have painful surgery every 3 months to lengthen their spine, which is held partly straight by a metal rod.  Their parents, who exhaustively take every measure possible to normalize life for their boys, have sought long for a researcher to find the mutated gene. They realize that hope of a medication to help the spine grow lies first in determining the biological pathway that is altered. Their grief of having all four children affected is a little abated, they tell us, by knowing the children can share their life-shaping experiences and by knowing that there is now a good opportunity to find the gene by comparing which genes variations are shared by all children, and hence possibly the culprit. We will analyze the 10 most likely causative shared genes and arrange for follow-up studies once the gene is found.

Results -

We successfully identified the gene BMPER as a novel cause for severe congenital scoliosis. We performed exome sequencing in one proband of a sibship of four with an undiagnosed skeletal dysplasia presenting with severe scoliosis requiring extensive surgical correction. We performed SNP array on the other siblings to determine regions of shared parental inheritance. Within these regions, only BMPER featured two damaging, rare variants. This gene also causes diaphanospondylodysostosis, a lethal disorder with some similar features.

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